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PubMed2003

Two new mutations in cis on (G)gamma chain of fetal hemoglobin: Hb F-Madrid [G gamma 50(D1)Ser-->Cys] and [G gamma 75(E19)Ile-->Thr].

We describe a new structural hemoglobin variant of (G)gamma with two amino acid replacements in cis found in the umbilical cord blood of a neonate in Madrid, Spain. The substitutions were identified on exon 2 of the (G)gamma globin gene, at codon 50 (T CT-->T GT) and at codon 75 (A TA-->A CA). We have named it Hb F-Madrid. The father of the propositus was the carrier of the same (G)gamma chain variant and, moreover, molecular study of alpha genes revealed the loss of an alpha gene (-alpha(3.7)/alpha alpha) both in the propositus and his mother.

Base Sequence↗
PubMed2002

Molecular and structural studies of the GM2 gangliosidosis 0 variant.

To determine the molecular basis of the GM2 gangliosidosis 0 variant, we constructed a three-dimensional structure of the human beta-hexosaminidase beta-subunit by homology modeling. It is composed of two domains, domains I and II, and has three disulfide bonds. C534 is located on an extra helix in domain II and forms a disulfide bond with C551. The extra helix is structurally located near domain I. C534Y, identified in a patient with the infantile form of the disease, was deduced to cause disruption of the disulfide bond, which results in a large conformational change of the extra helix, stabilizing the two domains. The drastic change in the protein structure results in a deficiency of the mature beta-subunit, and deficient activities of beta-hexosaminidases A (abeta) and B (betabeta), followed by abundant accumulation of GM2 ganglioside in the patient's cells. R505 is located on the eighth helix of domain II. R505Q, found in a patient with the chronic form of the disease, is predicted to influence the surface structure of the beta-subunit, although it does not affect the active site. The amino acid substitution causes a partial processing defect and decreased enzyme activities, which result in moderate accumulation of GM2 ganglioside in the patient's cells. The structural defects well reflect biochemical and phenotypic abnormalities of the disease.

Adult↗
PubMed1983

Three families with hereditary hemolytic anemia and pyrimidine 5'-nucleotidase deficiency: electrophoretic and kinetic studies.

Three new variants of pyrimidine 5'-nucleotidase (P5N) found in Japan were studied. They are characterized by slow electrophoretic mobility and a high Michaelis constant for cytidine 5'-monophosphate as has been described in previously reported cases, but are unique with respect to the thermostability test and in pH optima. P5N Kumamoto was thermostable and showed a markedly basic shift in the pH optimum. P5N Nagano was thermolabile and had a normal pH optimum. P5N Kurume was thermostable and showed a basic shift in the pH optimum. These data suggest that these variants have structural gene mutations and that they are clearly distinguished from previously reported cases.

5'-Nucleotidase↗
PubMed1985

Structural comparisons of two allelic variants of human placental alkaline phosphatase.

A simple immunosorbent purification scheme based on monoclonal antibodies has been devised for human placental alkaline phosphatase. The two most common allelic variants, S and F, have similar amino acid compositions with identical N-terminal amino acid sequences through the first 13 residues. Both variants have identical lectin binding properties towards concanavalin A, lentil-lectin, wheat germ agglutinin, phytohemagglutinin and soybean agglutinin, and identical carbohydrate contents as revealed by methylation analysis. CNBr fragments of the variants demonstrate identical high performance liquid chromatography patterns. The carbohydrate containing fragment is different from the 32P-labeled active site fragment and the N-terminal fragment.

Alkaline Phosphatase↗
PubMed1992

Structure and pathogenicity of individual variants within an immunodeficiency disease-inducing isolate of FeLV.

We previously described the molecular cloning of a replication-defective variant of feline leukemia virus (FeLV) that induced fatal immunodeficiency in cats. Eighteen proviruses have now been molecularly cloned from cats inoculated with the original isolate (FeLV-FAIDS) or its in vivo passages. Three were replication-competent and each of these was noncytopathic for the feline T-cell line, 3201. Replication of the prototype, FeLV-61E, in cats was associated with development of T cell tumors in some cats. The remaining 15 proviruses were replication-defective, but each of six of these tested was found to be cytopathic for 3201 cells when rescued with the noncytopathic helper virus, 61E. Three defective/helper virus mixtures were inoculated into cats and all induced fatal immunodeficiency, but with varied efficiency and kinetics. Each of these virus mixtures was attenuated relative to a mixture containing 61E and the intestine-targeted, FeLV-FAIDS-61C prototype defective molecular clone. Furthermore, one replication-competent virus chimera generated using the envelope and LTR of the defective pathogenic variant was incapable of inducing viremia in cats. The observed differences in the biological activity between the defective viruses could be attributed to no more than 10 scattered amino acid changes in envelope and either one or two nucleotide changes in the LTR.

Amino Acid Sequence↗
PubMed1985

Relationships of the Col plasmids E2, E3, E4, E5, E6, and E7: restriction mapping and colicin gene fusions.

Thirteen ColE plasmids representing the E2-E7 types have been compared by restriction mapping. Over 80% of their restriction sites were found to be similarly positioned, indicating that these plasmids share a common structure. Three variants are ColE2-CA42 and ColE7-K317, both of which contain 1.8-kb DNA segments in place of a 2.5-kb segment common to the other plasmids, and ColE6-CT14, which has an additional 5.0-kb DNA segment compared to the other plasmids. The colicin (col), immunity (imm), and colicin release (hic) genes of these plasmids have been localized to regions corresponding to those known for ColE3-CA38 and ColE2-P9, with the imm and hic genes adjacent to the 3' end of the col gene. Active colicin is produced from hybrid col genes containing 5' and 3' ends from different E-type plasmids. The 3'-termini of the fused col genes specify the colicin type.

Bacteriocin Plasmids↗
PubMed1987

A human-human hybridoma (Tr7E2) producing cytotoxic antibody to HLA-DQw1.

A human-human IgM (lambda) hybridoma antibody (called Tr7E2) was constructed by fusing Epstein-Barr virus-transformed cells from a multiparous woman with the human fusion partner KR12. By eosin exclusion microcytotoxicity the monoclonal antibody killed 12 of 13 human leukocyte antigen DQw1-bearing lymphoblastoid cells. No reaction was seen with any of 19 DQw1-negative cells. The single DQw1+ cell line that was not killed by Tr7E2 was the homozygous cell called 9WS 806 TAB (DR8,8; DQw1,1) of Japanese origin. The radioimmunoassay indicated that this result was probably not because of a decreased expression by this cell of DQ antigens, and these cells were killed by the mouse monoclonal antibody Genox3.53G2a5, reported to be specific for DQw1. Thus, the Tr7E2- cell line TAB probably expresses a novel structural DQw1 variant. Of 213 Norwegians, 107 were Tr7E2+ Genox+; none expressed only one of these epitopes. The putative split is, therefore, probably very rare in this population. Monodisperse magnetic polymer beads coated with Tr7E2 formed rosettes selectively with peripheral blood mononuclear cells from DQw1-positive individuals, suggesting a new approach to typing for class II antigens.

Antibodies, Monoclonal↗
PubMed1991

Structural characterization of a glycoprotein variant of human serum albumin: albumin Casebrook (494 Asp----Asn).

Albumin Casebrook is an electrophoretically slow genetic variant of human albumin with a relative molecular mass 2.5 kDa higher than normal albumin. It constitutes about 35% of total serum albumin in heterozygous carriers. The decrease in negative charge observed on incubation with sialidase suggested the presence of a carbohydrate moiety and the normalization of molecular weight following treatment with Endo-F indicated that this was an N-linked oligosaccharide. Partial acid hydrolysis and limited tryptic digestion established that the oligosaccharide was located in the C-terminal domain, between residues 367 and 585. Tryptic, chymotryptic and S. aureus V8 proteinase digestions were carried out and the resulting glycopeptides were purified on concanavalin A-Sepharose. Peptide mapping of bound and unbound fractions followed by amino acid composition and sequence analysis, established a point mutation of 494 Asp----Asn. This introduces an Asn-Glu-Thr N-linked oligosaccharide attachment sequence centered on Asn-494 and explains the increase in molecular mass. There was no apparent pathology associated with the presence of this new glycosylated albumin, which was detected in two unrelated individuals of Anglo-Saxon descent.

Amino Acid Sequence↗
PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗
PubMed2004

Protonmotive cooperativity in cytochrome c oxidase.

Cooperative linkage of solute binding at separate binding sites in allosteric proteins is an important functional attribute of soluble and membrane bound hemoproteins. Analysis of proton/electron coupling at the four redox centers, i.e. Cu(A), heme a, heme a(3) and Cu(B), in the purified bovine cytochrome c oxidase in the unliganded, CO-liganded and CN-liganded states is presented. These studies are based on direct measurement of scalar proton translocation associated with oxido-reduction of the metal centers and pH dependence of the midpoint potential of the redox centers. Heme a (and Cu(A)) exhibits a cooperative proton/electron linkage (Bohr effect). Bohr effect seems also to be associated with the oxygen-reduction chemistry at the heme a(3)-Cu(B) binuclear center. Data on electron transfer in cytochrome c oxidase are also presented, which, together with structural data, provide evidence showing the occurrence of direct electron transfer from Cu(A) to the binuclear center in addition to electron transfer via heme a. A survey of structural and functional data showing the essential role of cooperative proton/electron linkage at heme a in the proton pump of cytochrome c oxidase is presented. On the basis of this and related functional and structural information, variants for cooperative mechanisms in the proton pump of the oxidase are examined.

Animals↗
PubMed1988

Investigation of the tetramer-dimer equilibrium in haemoglobin solutions by high-performance size-exclusion chromatography on a diol column.

High-performance size-exclusion chromatography on a diol grafted column was applied to study the tetramer-dimer equilibrium in haemoglobin solution. Human haemoglobin A, isolated alpha A and beta A subunits and haemoglobin variants with structural modifications located at the interface between subunits were used as models. The elution volume of the subunits was found to deviate strongly from that expected from only a gel permeation mechanism and therefore ionic interactions are likely to participate in the protein retention. Experimental results and computer simulation indicate that the individual elution bands corresponding to the discrete components (tetramer, dimer, monomer) can be resolved under certain conditions. In general both the equilibrium and kinetic interconversion parameters must be considered. Single tetramer elution bands were observed from haemoglobin in the concentration range measurable, although the influence of dimers could be seen in the shape and shift of the profile. beta Chains showed resolved peaks for the tetramer-dimer forms.

Chromatography, Gel↗
PubMed2000

Applications of molecular biology techniques to transfusion medicine.

Other articles in this issue of Seminars in Hematology have reviewed the results of basic research in relation to the understanding of the genes, the molecular basis of blood group variants, and structural and functional aspects of the proteins carrying blood group antigens. Although molecular techniques are currently being used in a limited fashion in clinical laboratories, their application has far-reaching possibilities and undoubtedly will be soon applied more generally. We focus on two general areas: molecular genotyping for blood group antigens and their expression analysis in heterologous systems.

Blood Group Antigens↗
PubMed1998

The influence of base sequence on the immunological properties of defined oligonucleotides.

To assess the influence of base sequence on the immunostimulatory activities of DNA, cell binding and mitogenicity of a series of 30-mer phosphodiester oligonucleotides were tested using murine spleen cells. These compounds consisted of either a single base or a six base CpG motif in the context of 5' and 3' flanking sequences of each base. Among fluoresceinated oligonucleotides, (dG)30 had the highest binding of single base compounds tested while the presence of dG flanks increased binding of compounds with six base motifs, whether active on inactive. In assays of mitogenesis including incorporation of thymidine and uridine as well as expression of cell surface CD69, (dG)30 induced the highest responses among single base compounds. Among compounds with an active six base motif, the extent of proliferation varied with flanking sequence, with dG flanks producing the greatest stimulation in all assays tested. Together, these findings indicate that a variety of base sequences may affect the immunomodulatory properties of DNA, with the activity of dG sequences perhaps resulting from the formation of variant DNA structures.

Animals↗
PubMed1997

Effect of genetic variation on the fatty acid-binding properties of human serum albumin and proalbumin.

In the circulation, non-esterified fatty acids are transported by albumin which also facilitates their removal from donor cells and uptake into receptor cells. We have studied whether genetic variations in the albumin molecule can affect its in vivo fatty acid-binding properties. The fatty acids bound to 25 structurally different variants and to their wildtype counterparts, isolated from heterozygous carriers, were determined gas chromatographically. The variants were proalbumins, albumins with single amino acid substitutions and glycosylated or truncated albumins. In eight cases the total amount bound to the variants was diminished (0.4-0.8-fold), and in seven cases the load was increased to 1.3 or more of normal. Twenty-one fatty acids were quantitated, and for 19 alloalbumins significant deviations from normal were found. Usually, changes in total and individual fatty acid binding were of the same type, but several exceptions to this rule was found. The glycosylated albumin Casebrook showed the largest changes, the total load and the amount of bound palmitate was 8.6 and 14 times, respectively, the normal. The most pronounced changes and the majority of cases of increased binding were caused by molecular changes in domain III. Mutations in domain I, II and the propeptide resulted in smaller effects, if any, and these were often reductions in binding.

Amino Acid Sequence↗
PubMed2002

Cloning, expression and genomic structure of human LMX1A, and variant screening in Pima Indians.

LIM-homeodomain containing protein LMX1A activates transcription of the insulin gene. The human LMX1A gene maps to 1q22-q23, a region identified as a putative type 2 diabetes mellitus (T2DM) locus in several different populations. We analyzed LMX1A as a positional and biological candidate gene for T2DM in the Pima Indians, in whom a linkage of T2DM to 1q21-q23 has been previously reported. In the present study, we describe the cloning, expression and genomic organization of the LMX1A gene, which is composed of 11 exons spanning approximately 151 kb. In addition to a transcript encoding the predicted full-length protein of 382 amino acids, we identified two truncated cDNA forms produced via additional transcription start sites and alternative splicing. We identified seven single nucleotide polymorphisms (SNPs) throughout the LMX1A locus and determined allele frequency distributions in 150 diabetic and 150 unaffected Pimas. We did not find evidence for association of any LMX1A SNPs with T2DM and conclude that LMX1A does not contribute significantly to T2DM etiology in Pima Indians.

Alleles↗
PubMed1998

Procollagen N-proteinase and procollagen C-proteinase. Two unusual metalloproteinases that are essential for procollagen processing probably have important roles in development and cell signaling.

As soon as procollagen precursors of fibrillar collagens were discovered in the early 1970s, it became apparent that connective tissues must contain proteolytic activities that cleave the N-propeptides and the C-propeptides from procollagens. Isolation and characterization of the enzymic activities, however, proved to be unexpectedly difficult. Both proteinases are large and are synthesized in several different forms with polypeptide chains ranging in size from 70 kDa to about 130 kDa. The N-proteinase has the unusual property of cleaving the N-propeptides from type I and type II procollagens if the proteins are in a native conformation, but not if the proteins are partially unfolded so that the N-telopeptides are no longer in a hair-pin configuration. The C-proteinase specifically cleaves native and denatured types I, II and III procollagens. It also specifically cleaves a precursor of lysyl oxidase and laminin 5. Both enzymes and their variants have structures that place them in a large and expanding super-family of over 200 zinc-binding metalloproteinases. The larger of two forms of the N-proteinase contains an RGD sequence for binding through integrins and properdin repeats similar to those found in thrombospondin. The shorter 70 kDa form of the C-proteinase is identical to the protein that was previously identified as bone morphogenic protein-1. Both the 70 kDa C-proteinase and two larger forms are homologous to proteins that are expressed early in development in a variety of organisms, including Drosophila, sea urchin, and fish. Therefore, the data suggest that both the N- and C-proteinases have important biological functions in addition to the roles in the processing of procollagens.

Animals↗
PubMed1999

Protein engineering of alpha-amylase for low pH performance.

Industrial-scale starch liquefaction is currently constrained to operating at pH 6.0 and above, as the enzyme used in the process, Bacillus licheniformis alpha-amylase, is unstable at lower pH under the conditions used. There is a need to develop an enzyme that can operate at lower pH. Recent progress has been made in engineering the B. licheniformis enzyme for improved industrial performance. The availability of crystal structures and subsequent analysis of improved variants, in a structural context, is revealing common factors and a rationale to make further improvements.

Amino Acid Substitution↗